Codeine and 2-methyl-3-o-tolyl-4-quin-azolone analgesic composition



Aug. 28, 1962 E. E. HAYS ETAL 3,051,623

000mm: AND Z-METHYL-3-0TOLYL-4-QUINAZOLONEZ ANALGESIC COMPOSITION FiledApril 24, 1959 Q CODEINE SULFATE, 5o MG/KG Q CODEINE SULFATE, 5o M KPLUS ,20 METHYL ATROPINE, 5 MG/KG 5% CODEINE REsIN COMPLEX, 75 MG/KG 13[I] CODEINE REsIN coMPLEx, 75 MG/KG 3 PLUS METHYL ATROPINE RESIN CDcoMPLEx, s MG/KG SI0 r [N FIGI- POTENTIATION OF CODEINE ANALGESIA BYMETHYL ATROPINE 5 4O I I 30- E] cooEINE AS RESIN coMPLEx, Ioo MG/KG (j I33 7 Q CODEINE AS REsIN COMPLEX, I00 MG/KG q PLUS QUINAZOLONE REsINCOMPLEX, 2o MG/KG S cooEINE AS RESIN COMPLEX, I00 MG/KG Iw PLUSQUINAZOLONE REsIN coMPLEx, 66 MG/KG F|G.2- POTENTIATION OF CODEINEANALGESIA BY UIN ZOLONE Q A .Zfiz/nfors.

521051157 22 Leonard M20 elsorz.

United States Patent l 3,051,623 (ZGDEDJE AND 2-METHYL-3-G-TOLYL-4-QUIN-AZGLONE ANALGESHC COMPGSHIGN Edwin E. Hays and Leonard Michelson,Rochester, N.Y.,

assignors to Wallace and Tiernan inc, a corporation of Delaware FiledApr. 24, 1950, Ser. No. 808,622 1 Claim. (Cl. 16767) This application isa continuation-in-part of our copending application, Serial No. 706,252,filed on December 31, 1957, now abandoned.

This invention relates to therapeutic compositions, and moreparticularly to therapeutic compositions containing codeine andcodeine-like drugs which produce a longeracting and potentiatedresponse. More particularly, the compositions of the present inventioncontemplate the inclusion of codeine, and codeine-like compounds whichare potentiated by the addition of quinazolones, which are described andclaimed in our co-pending application, Serial No. 706,252. The inventionrelates to compositions including codeine, and codeine-like compoundsper se, with the above mentioned quinazolones per se, and also includessuch compounds in the form of resinate complexes, as will be more fullydescribed hereafter.

Codeine has long been used in the medical field for its analgesicproperties. While it has only moderate oral analgesic properties, it hasbeen employed, particularly in combination with aspirin, phenacetin, andcaffeine compounds. Such mixtures, however, must be administered everyfew hours in order to provide a patient with any prolonged release frompain. As a result, the medical profession has long sought a preparationwhich would produce a long-acting and potentiated response.

An object of the present invention is to provide therapeuticcompositions which have a longer-acting and more powerful analgesicetfect than codeine alone.

It is another object of the present invention to provide compositionswhich are delayed in their absorption with the resulting reducedtoxicity and prolongation of the drug action, such compositions beingobtained by combining codeine and the quinazolones mentioned above inthe form of a resin complex or resinate.

in accordance with the present invention, the above and other objectswhich will become apparent hereinafter, are accomplished by acomposition comprising codeine, or a codeine-like drug, and one or moreof the quinazolones of the type mentioned below.

We have also found that methyl atropine will potentiate the analgesicactivity of codeine.

Suitable quinazolone compounds are 2-methyl-3-o-tolyl-4-quinazolone,2-rnethyl-3-phenyl-4-quinazolone, 2-ethyl-3-phenyl-4-quinazolone,2-ethyl-3-o-tolyl-4-quinazolone, Z-ethyl-3m-tolyl-4-quinazolone,2-n-pro-pyl-3-phenyl-4-quinazolone, 2-n-propyl-3-o-tolyl-4-quinazolone,2-methyl-3-lauryl-4-quinazolone.

The acid addition salts of these compounds are also included within thepresent invention. of the acid addition salts of the free base withinorganic or organic acids which may be prepared by the methodshereinafter described are the hydrochloride, hydrobromide, hydroiodide,sulfate, phosphate, maleate, acetate,

than the resinates made with carboxylic acid cation exchange resins.

Some examples sodium o-nitrobenzoate in acetone.

65 citrate, oxalate, succmate, benzoate, tartrate, phthalate,

I .Of benzene.

3,051,623 Patented Aug. 28, 1962 To facilitate a fuller and morecomplete understanding of how the principles of this invention may beapplied, certain specific examples follow herewith. It is clearly to beunderstood, however, that these examples are provided by way ofillustration only, and that they are not to be construed as imposing anylimitations upon the invention as defined in the subjoined claims.

PREPARATION OF QUINAZOLONES Example 1.2-Methyl-3-Ph enyl-4-Quinaz0l0ne135 gms. of N-phenyl-acetamide were refluxed for 4 hours with gms. ofthionyl chloride and one liter of benzene. The benzene and excessthionyl chloride were stripped oil under vacuum. The residue wasdissolved in 350 cc. of acetone and added to 210 gms. of sodiumo-nitro-benzoate in acetone. After an hour at room temperature, thereaction mixture was concentrated and the residue extracted with hotwater to give 250 gms. of N- phenyl 1 N-acetyl-onitrobenzamide. TheN-phenyl-N- acetyl-o-nitrobenzamide was dissolved in 2500 cc. of alcoholand heated to reflux. A solution of 1750 gms. of Na S O in 5500 cc. ofwater was added dropwise. The alcohol was stripped off, and the residuepoured into water, filtered, washed with hot water, and the product wasextracted with warm concentrated HCl. The free .base was obtained byneutralizing with HCl solution in alkali. Yield200 gms.

Example 2.-2-Ethyl-3-Phenyl-4-Quinazolone 149 gms. of N-phenylpropionamide were refluxed for 4 hours with 120 gms. of thionyl chlorideand one liter of benzene. The benzene and excess thionyl chloride werestripped ofi under vacuum. The residue was dissolved in 375 cc. ofacetone and added to 210 gms. of sodium o-nitrobenzoate in acetone.After one hour at room temperature, the reaction mixture wasconcentrated and the residue extracted with hot water to give 270 gms.of Nphenyl-N-propionyl-o-nitro benzamide. This was dissolved in 2700 cc.of alcohol and heated to reflux. A solution of 1750 gms. of Na S O in5500 cc. of water was added dropwise. The alcohol was stripped off andthe residue poured into water, filtered, washed with hot water and theproduct was extracted with warm concentrated HCl. The free base wasobtained by neutralizing the HCl solution with alkali. Yield220 gms.

Example 3.-2-Ethyl-3-0-T0lyl-4-Quinazolone 173 gms. ofN-o-tolyl-propionamide were refluxed for 4 hours with 120 gms. ofthionyl chloride and one liter of benzene. The benzene and excessthionyl chloride were stripped ofi under vacuum. The residue wasdissolved in 400 cc. of acetone and added to 210 gms. of sodiumo-nitrobenzoate in acetone. After one hour at room temperature, thereaction mixture was concentrated and the residue extracted with hotwater to give 280 gms. of

N-o-tolyl-N'propionyl-o-nitrohenzamide. This was dissolved in 2800 cc.of alcohol and heated to reflux. A solution of 1750 gms. of Na S O in5500 cc. of water was added dropwise. The alcohol was stripped off andthe residue poured into water, filtered, washed with hot water and theproduct was extracted with warm concentrated HCl. The free base wasobtained by neutralizing the HCl solution with alkali. Yield230 gms.

Example 4.2-Ethyl-3-m-Tolyl-4-Quinazolone 173 gms. ofN-m-tolyl-propionamide were refluxed for 4 hours with 120 gms. ofthionyl chloride and one liter The benzene and excess thionyl chloridewere stripped off under vacuum. The residue was dissolvedin 400 cc. ofacetone and added to 210 gms. of After one hour at room temperature, thereaction mixture was concentrated oxychloride.

will depend on the nature of the reactants.

and the residue extracted with hot water to give 280 guns. ofN-m-tolyl-N-propionyl-o-nitrobenzamide. This was dissolved in 2800 cc.of alcohol and heated to reflux. A solution of 1750 gms. of Na S O in5500 cc. of water was added dropwise. "Ihe alcohol was stripped off andthe residue poured into water, filtered, washed with hot water and theproduct was extracted with warm concentrated HCl. The free base wasobtained by neutralizing the HCl solution with alkali. Yield230 gms.

Example 5 .2-n-Propyl-3-Phenyl-4-Quinazolone 163 gms. of N-phenylbutyramide were refluxed for 4 hours with 120 gms. of thionyl chlorideand one liter of benzene. The benzene and excess thionyl chloride werestripped oil under vacuum. The residue was dis solved in 400 cc. ofacetone and added to 210 gms. of sodium o-nitro-benzoate in acetone.After one hour at room temperature, the reaction mixture wasconcentrated and the residue extracted with hot water to give 280 gms.of N-phenyl-N-butyryl-o-nitrobenzarnide. This was dissolved in 2800 cc.of alcohol and heated to reflux. A solution of 1750 gms. of Na S O4 in5500 cc. of water was added dropwise. The alcohol was stripped off andthe residue poured into Water, filtered, washed with hot water, and theproduct was extracted with warm concentrated HCl. The free base wasobtained by neutralizing the HCl solution with alkali. Yield-230 gms.

Example 6 .2-n-Pr0pyl-3-0-T0lyl-4-Quinazolone 177 gms. of N-o-tolylbutyramide were refluxed for 4 hours with 120 gms. of thionyl chlorideand one liter of benzene. The benzene and excess thionyl chloride werestripped off under vacuum. The residue was dissolved in 430 cc. ofacetone and added to 210 grns. of sodium'o-nitro-benzoate in acetone.After one hour at room temperature the reaction mixture was concentratedand the residue extracted with hot water to give 290 gms. ofN-o-tolyl-N-butyry l-O-nitrolbenzamide. This was dissolved in 2900 cc.of alcohol and heated to reflux. Added dropwise was a solution of 1750gms. of Na S O in 5500 cc. of water. The alcohol was stripped off andthe residue poured into water, filtered, washed with hot water, and theproduct was extracted with warm concentrated HCl. The free base wasobtained by neutralizing the HCl solution with alkali. Yield240 gms.

In general, the compounds of the present invention may be prepared byeither of two methods. The first, in general, involves the heating ofN-acyl-o-amino-cyclic carboxylic acid with a primary amine in a suitablesolvent in the presence of phosphorus trichloride or phosphorus Thephosphorus chloride, preferably diluted with a small amount of thesolvent employed, is added slowly and portionwise to the solution of theother components. The degree of heating to efiect the reactionPreferably, the temperature is one at which the reaction mixturerefluxes, although lower temperatures may be employed.

The second method involves the preparation of the compounds, such asshown in Examples 1-6, by the reaction of the corresponding amide withthionyl chloride in a suitable solvent, and the addition of a benzoateto form the corresponding amide, which is then converted to the desiredquinazolone.

In general, it has been found that doses between 10 and 400 mgs. areeffective for producing the therapeutic results set forth above. Inparticular, it has been found that the above compounds, when absorbedupon and ionically bound with a sulfonic acid cation exchange vresin,produce a long acting effect for a period of at least 8 to 12 hours.

An example of dosage form. of 2-rnethyl-3-ortho-tolyl- 4(3H)-quinazolone bound on a sulfonic acid ion exchange resin is asfollows:

To 370 gms. of moist Amberlite IR120 resin (225 gms. of dry resin)suspended in distilled water was added for reaction with the compoundsdisclosed herein to provide the pharmaceutically effective adsorptioncompounds. The term sulfonic acid cation exchange resin is intended toinclude the phenol-sulfonic acid cation exchange resins and thecarboxylic-sulfonic acid cation exchange resins, as well as the ordinarysulfonic acid cation exchange resins. However, particularly satisfactoryresult-s have been obtained with the sulfonic acid cation exchangeresins disclosed in DAlelio Patent No. 2,366,- 007, such resins beingsulfonated polymerizates of polyvinyl aryl compounds. Other suitablecation exchange resins are disclosed in US. Patents Nos. 2,204,539;2,338,- 159; and 2,729,607.

The cross linkage of the sulfonic acid resins is suitably between 3percent and 17 percent, and preferably between 5 percent and 10 percent,to obtain the most effective slow rate of diffusion of stomach andintestinal juices into the resin. The particle size of the resins is oflesser importance, but improved slowing down efiect is obtained with aparticle size between 20 to mesh over that of finer particle, such as200 mesh.

An illustrated formula of a suitable cation exchange resin adsorptionproduct of an amine is given below, A representing a resin nucleus:

The resin adsorption compounds of this invention are preferablysubstantially saturated with the amine. Saturation will generally runfrom about 30 percent to 50 percent, depending upon the amine and thetime of contact with the sulfonic acid cation exchange resin. However,the resin does not necessarily have to be saturated, and as little as 10percent and less of the adsorption amine can be used.

The resin adsorption products can be readily made by agitating theingredients suspended in water until the reaction is complete.

In the examples, IR-120 refers to a sulfonic acid cation exchange resin,7 percent to 8 percent cross-linked, having a particle size such thatsubstantially all particles pass through a 20 mesh screen and areretained on a 50 mesh screen, and made in accordance with Example 1 ofUS. Patent No. 2,366,007, except that 7.5 parts of divinyl benzene areused instead of the 10 parts. XE-69 refers to the same resin as I-R120except that substantially all particles pass through an 80 mesh screenand are retained on a mesh screen.

PREPARATION OF CODEINE RESIN COMPLEX Example 7 Place 34.66 lbs. ofAmberlite Resin XE-69 in sack in the reaction tank. 35 gallons ofdeionized water is added and then hydrochloric acid, 'C.P. conc., isadded to bring pH to one to 2 under agitation. Continued agitation for30 minutes, drain tank, add 25 gallons of deionized water and draintank; add 35 gallons of deionized water. Next, 11.82 lbs. of codeine isadded and then is agitated for 3 hours and allowed to stand overnight.Supernatant liquid is removed and 35 gallons of water added and agitatedfor 15 minutes, allowed to stand, and supernatant decanted. Repeat 3more times. The cake is sucked to dryness, transferred to trays, anddried at 128 F. overnight. Cake is then fed through Fitzpatric with No.2 screen.

PREPARATION OF METHYL ATROPINE-RESIN- COMPLEX Example 8 Add 220 gms. ofXE-69 resin to one liter of 3 percent hydrochloride in water and mix for30 minutes. Decant, wash, and resuspend in 3 liters of water. Add 95gms. of methyl atropine nitrate and stir slurry for 3 hours. Allow tostand overnight, then stir for additional 2 hours. Decant, wash, andoven dry at 60 F.

50 nag/kg. of codeine sulfate showed efiective analgetic response(greater than 3 Asec.) at 30 minutes but not after 90 minutes. At 75nag/kg. potency was similar but efiective analgesia lasted 90 to 180minutes.

75 mg./kg. of codeine resinate (sulfuric acid cation exchange adsorptioncompound) produced efiective analgesia equal in intensi-ty to that of 50mg./kg. of codeine as sulfate, but of much longer duration (4-12 hrs.)than that of even 75 mg./kg. of codeine as sulfate. Hence, prolongationof effect is attained.

FIGURE 1 shows the potentiation of codeine analgesia by the addition ofmethylatropine, and methylatropine as the resin complex. Methylatropineat 5 and mg./kg. as the nitrate enhanced the analgetic action of 50mg./kg. of codiene as sulfate. 9 mg./kg. of methylatropine as resinatepotentiated the analgetic effect of 75 mg/kg. of codiene as resinate.Methylatropine, itself, has substantially no analgesic activity.

FIGURE 2 shows the potentiation of codiene analgesia by the addition ofquinazolone compounds described herein, both alone and as resincomplexes. The quinazolones which have no analgetic properties in dosesof mg./kg. increased the analgetic activity of 50 and 100 mg./kg. ofcodeine as sulfate. When both codeine (100 rug/kg.) and the quinazolones(20 mg./kg.) were given as resinates, the analgesic activity wasincreased by an average factor of 4.3. Increase of the quinazolone doseto 66 mg. kg. increased tht factor to 6.4.

The specific quinazolone compound shown in FIG. 2 was2-methyl-3-orthotolyl-4-quinazolone. However, similar potentiation wasobtained with other quinazolones above mentioned and the effect isbelieved to be a general one for analgesic morphine compounds andtranqnilizing quinazolones.

The prolongation of therapeutic activity of a number of drugs has beenachieved by reacting them with appropriate synthetic ion exchangers.Where the drug resinate exhibits prolongation of action, it is lesstoxic than the soluble salt form when compared on a free drug basis.

The above results were obtained by the DAmour and Smith apparatus andtechnique for aualgesiometn'c measurement in the rat. A 300 watt A.C.projection lamp at 95-100 volts as a heat source was used. Two groups of10 animals each were placed in the dolorometer and their response timemeasured. The voltage was adjusted so that mean baseline response timewas of the order of 2 sec. The voltage was then kept constant throughoutthe experimental period. The pre-treatment response time of each animalWas measured 3 times. The average of second and third values was takenas the animals baseline response time. Drugs were given by gavage asaqueous solutions or suspensions at a 5 percent dose volume. Responsetime was measured minutes after dosing and then at intervals usually onehour apart. Ten seconds was the maximal stimulus time in anymeasurement. For each animal, baseline response time was subtracted fromeach post-dose response time (:A see). This value less 3A sec. (thecriterion of minimum analgesia) was multiplied by hours elapsed afteradministration of the dose (:A sec. hr.) and totaled (6A sec. hr.) foreach animal. The mean and stand. dev. of eA sec. hr. of test and controlgroups were calculated. Students t test was used to demonstrate whetherthe difference of the means was statistically significant. Rat-toratvariation is large as evidenced by large stand. dev. Day-to-dayvariation is greater than dose-to-dose variation (Table 1). Accordingly,a reproducible log doseefiect curve could not be derived. Each test is a1 x 1 direct comparison.

The active medicaments of the present invention, as described above, maybe in dosage-unit form for a single therapeutic dose, in smaller unitsfor multiple doses, or in larger units for division into single doses.Obviously, in addition to the therapeutic effective agents ormedicaments, there may also be present excipients, binders, fillers,extenders, and other therapeutically inert ingredients necessary in theformulation of active medicaments into a pharmaceutical preparation indosage-unit form.

Since various changes and modifications may be made in the invention,certain preferred embodiments of which have been herein described, it isthe intention that such changes and modifications as are within thescope of the appended claim shall be considered as part of theinvention.

We claim:

Therapeutic compositions having analgesic properties comprising amixture of a substance of the group consisting of codeine and itspharmaceutically acceptable acid addition salts, with a substance of thegroup consisting of 2-methyl-3-o-tolyl-4-quinazolone and itspharmaceutically acceptable acid addition salts, said quinazolonecompound and codeine compound being present in a ratio 20 to 66 parts byweight of quinazolone to 50 to parts by weight of codeine.

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